Nature: For the deadliest pancreatic cancer, survival is a complex issue

Pancreatic ductal adenocarcinoma (PDAC) is the most common and deadly form
of pancreatic cancer.
The 5-year survival rate for patients with PDAC was only 7.
1%.

All cancers are different
.
A unique feature of PDAC is the extensive tumor adhesion hyperplasia or fibroconnective tissue within the tumor, which is caused
by infiltration of tumor blocks by fibroblasts and their secreted extracellular matrix.
The main component of the matrix is type I collagen or Col 1, a protein widely used in the human body that forms the basic structure
of bones, skin, blood vessels, and connective tissue.

The effects of Col 1 on PDAC development and its response to treatment have been hotly debated by researchers, with some arguing that Col 1 promotes tumor growth and spread, while others believe it limits tumor growth and protects cancer cells from immune attack
.

In a new study published October 5, 2022, Dr.
Hua Su is a postdoc
in the lab of senior author Michael Karin.
Dr.
Fei Yang, Ph.
D.
, Distinguished Professor of Pharmacology and Pathology at the University of California, San Diego School of Medicine, and Dr.
Beicheng Sun, Nanjing University School of Medicine, combined to resolve the debate, showing that the number of Col 1 in tumors does not matter, what matters is the quality and nature
of the tumor.

Specifically, they report that Col 1 cleavage by matrix metalloproteinase (an enzyme that breaks down matrix proteins, such as collagen) stimulates tumor growth, while intact and uncut Col 1 inhibits tumor growth
.

In addition, the severed Col 1 activates a signaling pathway by binding to a receptor protein called DDR1 that stimulates pancreatic cancer cells to produce energy
.
Non-lysis Col 1 inhibits this pathway
by inducing the degradation of DDR1.
”

The study was conducted using a mouse model and a novel culture system in which PDAC cells were plated on
an extracellular matrix containing dividing or non-dividing Col 1.

The authors say these findings have important clinical implications
.

The relative number of cleavage versus non-cleavage Col 1 in human PDAC interstitial or connective tissue strongly affects the survival
of patients after surgical resection.
Those whose tumors were rich in sheared Col 1 and cancer cells expressing high levels of DDR1 did not progress well, with most patients dying from the disease
within two years of surgery.

The patient group, which made up 75 percent of the 106 patients, was part of the study and the cancer specimens used were provided
by Dr.
Beicheng Sun of the Drum Tower Affiliated Hospital of Nanjing University School of Medicine in China and colleagues.

In contrast, 25 percent of tumors predominantly contained non-cleft Col 1 with low levels of DDR1 expression had a better chance of
survival.

"This work is important because it provides a simple approach to patient stratification and shows that patients with high levels of shear Col 1 and DDR1 expression require more aggressive postoperative treatment," Karin said
.

"It also provides evidence that the most effective treatment for this class of patients should include DDR1 inhibitors or key components of their signaling pathways, the activation of which leads to an increase in the number of mitochondria in PDAC cells, which are the cell's power plants
.
"

In addition to DDR1 inhibitors, which have not yet been clinically used, the authors propose another treatment option, the U.
S.
Food and Drug Administration-approved antibiotic tigecycline, which inhibits mitochondrial protein synthesis and reduces the amount of energy-producing PDAC mitochondria, which is effective
for mice carrying PDAC.